Radiopharmaceuticals are widely used to evaluate cardiac function. Among the radioactive agents employed are, for example, .sup.99m Tc-labeled human serum albumin and .sup.99m Tc-labeled red blood cells for determination of cardiac blood volume, left ventrical wall motions and, ejection fractions. Evaluation of coronary blood flow can be done with radioactive inert gases, such as Xenon-133 and Krypton-85, or with radioactive labeled particles, e.g. .sup.99m Tc-macroaggregated albumin.
Radionuclides that are often considered analogues of potassium have been used for myocardial perfusion studies. Of these, .sup.201 Tl.sup.+ is presently the agent of choice. The mechanism of thallium uptake may be via the Na-K ATP-ase pump. Myocardial infarctions or reduced coronary blood flow will cause a decrease in the uptake of K.sup.+ or .sup.201 Tl.sup.+ in underperfused cardiac muscle. Infarcts or ischemic myocardium will be visualized as areas of low .sup.201 Tl.sup.+ activity. This type of study is called "cold spot" imaging. "Cold spot" imaging can also be done using labeled fatty acids, e.g. .sup.11 C-palmitate and .sup.123 I-fatty acids, and recent work indicates lipophilic cationic .sup.99m Tc complexes may be used.* FNT *Science, 214, 85 (1981)
Several agents have been shown to localize in infarcted myocardial tissue. Because the activity is concentrated in the damaged portions of the heart, this type of study is called "hot spot" imaging. These agents have proven to be more sensitive than "cold spot" imaging for the detection of myocardial infarcts.
Many non-technetium agents have been proposed for "hot spot" cardiac imaging. Thus, .sup.131 I-Rose Bengal, .sup.203 Hg-chlormerodrin, .sup.67 Ga-citrate, and .sup.203 Hg-diiodomercurihydroxyfluorascein have been suggested. However, these are generally not used because of the popularity of Tc-99m-agents.
Many organ scanning agents have been replaced with complexes of Technetium-99m. This nuclide has ideal physical properties (T.sub.1/2 =6 hour, gamma photon of 141 kev) for imaging. In addition, it is readily available because of the Mo-99/Tc-99m generators. Thus, the majority of imaging is now done using Tc-99m.
Technetium-99m is obtained from generators in the +7 oxidation state as the pertechnetate ion (TcO.sub.4.sup.-). In order to form a complex, Tc must be reduced to a lower oxidation state, i.e. +3, +4 or +5. Although other reducing agents can be used, Sn.sup.2+ has been employed most often. Thus, Tc-99m complexes can be formed by reduction of TcO.sub.4.sup.- using Sn.sup.2+ in the presence of a complexing agent. This is usually done in an aqueous saline solution that is suitable for intravenous injection.
Commercial complexing agents are sold as "radiopharmaceutical kits." A "kit" consists of an evacuated vial containing the complexing agent, a reducing agent, and possibly a buffer and stabilizers. To prepare the Tc-99m complexes, a few milliliters of sodium pertechnetate solution in saline is injected into the vial. The resultant solution is used for imaging.
Various .sup.99m Tc-chelates have been shown to accumulate in infarcts.* Thus, .sup.99m Tc-hydroxyethylenediphosphonate, .sup.99m Tc-methylenediphosphonate, .sup.99m Tc-glucoheptonate have been tested, some of which also show high bone uptake. FNT *J. Nuclear Med., 17, 534 (1976)
The most widely used agent for "hot spot" cardiac imaging is .sup.99m Tc-pyrophosphate**. Although many of the .sup.99m Tc-phosphates and phosphonates have an infarct to normal myocardium ratio comparable to .sup.99m Tc-pyrophosphate, the latter is preferred because of its relatively high infarct to bone ratio when compared to other .sup.99m Tc bone seeking agents and thus, there is less interference from the ribs and sternum.*** FNT **Radiology, 110, 473 (1974) FNT ***Seminars in Nuclear Medicine, Vol. IX, No. 4, 241 (1979)
Although .sup.99m Tc-pyrophosphate is the agent of choice to image acute myocardial infarcts, it still presents problems. For example, interference due to uptake in overlying skeletal structures, the inability to detect recent infarcts and the relatively slow blood clearance limit the utility of .sup.99m Tc-pyrophosphate. Therefore, a need still exists for new improved agents to image cardiac infarcts.
Certain new stable organic complexing agents for Tc-99m which are methylenephosphonic acid derivatives of dicyclopentadienebis(methylamine) have been disclosed as improved skeletal imaging agents. These are disclosed in our patent application U.S. Ser. No. 505,665 filed June 20, 1983, entitled "Radioactive Metals Complexed with Phosphonate Derivatives of Dicyclopentadienebis(methylamine)".
The same complexes have now been determined to be excellent radio imaging agents for damaged cardiac tissue.